NSAIDs on CV conditions Mechanisms and Efficacy Hasom (Rachel) Lee, Rong Shan Liu, Stephanie Li, Joshua-Ryan Wye-Yan Heung PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

What are NSAID’s? Non-Steroidal Anti-Inflammatory Drugs Common over the counter drug Analgesic (painkiller), antipyretic (lower fevers), anti- inflammatory properties skuid

NSAID

Traditional Uses Osteoarthritis Low back pain Headache Rheumatoid Arthritis Mild pain relief

Aspirin for Cardiovascular Therapy Anti-thrombotic drugs that prevent cardiovascular events Dose: mg/day Most common: 81mg/day Adverse Reactions: GI damage (major bleeding) Associated with higher doses Economic implications recommended-for-patients-at-high-risk-for-heart-disease

Mechanism of NSAIDs

Phospholipid Arachidonic Acid Prostaglandin H 2 PGE 2 TXA 2 COX (PGH synthase) NSAID NSAID Mechanism

Platelet Phase- Normal State platelet endothelium Factor VIII and von Willebrand Factor (vWF)

Platelet Phase - Adhesion platelet exposed collagen

Platelet Phase - Activation Activated platelet releases: Fibrinogen (forms a mesh around the platelet as the scaffold for platelet binding) ADP (binds to P2Y, increase in intracellular [Ca2+]) COX-1 synthesizes TXA2 (binds to thromboxane- prostanoid receptor) Result: Platelet shape change (disc to round with extensions) Maturation of GPIIa/IIIa (fibrinogen receptor) Net Result: platelet plug formation

COX-1 and COX-2

Clinical Evidence: Aspirin Therapy in the Secondary Prevention of Cardiovascular Disease Study design: Meta-analysis Number of studies included: 16 secondary prevention studies Population: individuals at high average risk Results: Decreased in risk of recurrent major coronary events: 20% Decreased in risk of recurrent stroke: 19%

Adverse Effects to Consider in Aspirin Therapy ●Aspirin therapy may not be right for you; always consult a doctor first ●Possible adverse effects:  Damage to the protective mucous layer in the GI tract  Lead to increased risk of GI ulcers and bleeding  How?  No formation of prostaglandins  Prostaglandins modulate many aspects of mucosal defense

inhibition

Comparison of NSAIDs (Aspirin) and Warfarin Anticoagulant, extrinsic pathway, vitamin k antagonist Indirectly targets clotting factor II, VII, IX, X By competitively inhibiting vitamin K epoxide reductase and Vitamin K quinone reductase -> decrease in active vitamin KH2 Adverse effects : hemorrhage, necrosis of soft tissue, teratogenicity (birth defects) Reverse adverse effects: stop giving warfarin, give vitamin K and prothrombin Do not consume with NSAIDs No magic bullet, different drugs for different patients

Why We (Future Pharmacists) Care? Many NSAIDS - such as aspirin - are over-the-counter drugs Help prevent people from purchasing aspirin to treat CV events unless a doctor have recommended it to them Helps reduce the chance of adverse effects

Summary NSAIDs: Non-Steroidal Anti-Inflammatory Drugs NSAIDs exert their anti-inflammatory and anti-thrombotic effect through COX inhibition Aspirin acetylates Ser 530 on COX. This covalent modification permanently blocks the enzyme. Clinical evidence that support the use of daily aspirin associated with secondary prevention cardiovascular Adverse effects of aspirin therapy: mucosal injury and bleeding

References Antithrombotic Trialists' (ATT) Collaboration. (2009). Aspirin in the primary and secondary prevention of vascular disease:collaborative meta-analysis of individual participant data from randomized trials. Lancet. 373: Casado-Arroyo, R., Sostres, C., & Lanas, A. (2013). Optimizing the use of aspirin for cardiovascular prevention. Drugs. 73(8): Dorsam RT, Kunapuli SP. (2004). Central role of the P2Y12 receptor in platelet activation. J Clin Invest. 113(3): Flower RJ. (2003). The development of COX2 inhibitors. Nat Rev Drug Discov. 2(3): Gasparyan, A. Y., Watson, T., & Lip, G. Y. H. (2008). The role of aspirin in cardiovascular prevention. Journal of the American College of Cardiology. 51(19): Iwamoto J, Yoshifumi S, Honda A, & Matsuzaki Y. (2013). Clinical features of gastroduodenal injury associated with long- term low-dose aspirin therapy. World J Gastroenterol.19(11): 1673–1682. Mayhew, M.S. (2010). Aspirin for preventing cardiovascular damage. Journal for Nurse Practitioners. 6(2): Sadler JE. (1998) Biochemistry and genetics of von willebrand factor. Annu Rev Biochem. 67: (1994). Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet. 343: